Guanylhydrazone Salts, Compositions, Processes of Making, and Methods of Using

ABSTRACT

The invention relates to pharmaceutically acceptable salts of guanylhydrazone-containing compounds, for example, Semapimod. The invention also relates to pharmaceutically acceptable compositions comprising the salts and methods for their use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.Nos. 60/582,532, filed Jun. 25, 2004, and 60/601,992, filed Aug. 17,2004, the entire contents of each of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to the field of pharmacology. In oneaspect, the invention is directed to improved salts of guanylhydrazonecompounds. In another aspect, the invention is directed to theformulation of pharmaceutical compositions containing improved salts ofguanylhydrazone compounds. The guanylhydrazone salts may be used forpreventive or therapeutic regimens or for the identification ofcandidate compounds for producing effective drugs having increased ormodulated solubility in water or a neutral solution for enhancing ormodulating bioavailability.

2. Related Art

United States Patent Application Publication No. 2004/0043079 to D'Souzarelates to microencapsulation as a delivery vehicle for a drug. Theguanylhydrazone compound Semapimod is disclosed in one embodiment.

United States Patent Application Publication No. 2003/0134904 toGiordano et al. relates to guanylhydrazone compounds for inhibitingRNase P activity.

United States Patent Application Publication No. 2003/0203969 to Bevecet al. relates to pharmaceutically active aromatic guanylhydrazonecompounds.

United States Patent Application Publication No. 2002/0028851 to Bianchiet al. relates to guanylhydrazone compounds and their uses to treatinflammatory conditions.

U.S. Pat. Nos. 6,673,777 and 6,143,728 to Tracey et al. relate toguanylhydrazone compounds and their uses for treating diseasesassociated with T cell activation.

U.S. Pat. Nos. 6,248,787; 6,180,676; 6,022,900; 6,008,255; 5,859,062;5,854,289; 5,849,794; 5,753,684; 5,750,573; and 5,599,984 all to Bianchiet al. relate to guanylhydrazone compounds and their uses to treatinflammatory conditions.

All references cited herein are incorporated by reference for allpurposes.

BACKGROUND OF THE TECHNOLOGY

Solubility in solution, either for a drug compound with a recognizedactivity or for a drug candidate compound, is almost always requiredbefore the compound can be analyzed or significant bioavailabilityachieved. Solubility in water or some aqueous or neutral solution isdesirable as high solubility eases molecular pharmacology screening aswell as biodistribution.

In vitro studies involving such aspects as receptor binding, enzymeinhibition, and cell cultures and studies with isolated organs are allfacilitated when the compound is made soluble in H₂O or other neutralmedia. When testing highly water insoluble material for in vitro assays,the common procedure to attain water solubility is to prepare a solutionusing an organic solvent (DMSO, polyethylene glycol, EtOH, etc.) andthen proceed to various aqueous dilutions. In following this regimen,there is always the possibility that the compound will precipitate outduring a dilution. Furthermore, any precipitation may not be properlyconsidered if it is not noticeable or the precipitate easily adheres tothe wall of the testing vessel.

Most organic acids or bases are only poorly soluble in water, whereasmany corresponding salts render the drug substance ionized in H₂O andhence made water soluble. Salts that are soluble in water are alsoideally suited for the preparation of injectable sterile aqueoussolutions. Also, fast dissolution of the active principle contained insolid dosage forms, such as for quick release tablets or hard-gelatinecapsules will rely on the aqueous solubility of the drug.

When considering in vivo testing, solubility in H₂O facilitates allstudies in which parenteral administration is required. Inpharmacokinetics, a reliable determination of absolute bioavailabilityvia oral administration is needed before a comparison is possible withan amount administered intravenously because a dose entering the systemby the parenteral route is a precisely known reference. Aqueoussolubility is particularly important in toxicity studies wherein thedigestibility of a compound in an animal will leave uncertainty as towhether an insoluble compound is either toxic or just incompletelyabsorbed.

On a therapeutic level, the major concern for finding a water-solubledrug resides in the possibility this solubility provides for intravenousadministration. The water solubility of a drug is particularly importantin drugs for emergency treatments that will permit therapeutic plasmalevels to be reached in a very short period of time. Intravenousadministration is often the only access available when a patient isotherwise incapacitated in an operation or some emergency situation.Also, water solubility is needed for several types of pharmaceuticaldosage formats. Apart from parenteral injection or infusion, watersolubility is important for producing aqueous drops for ocular or nasaladministration, or aqueous syrup for oral administration.

For oral consumption of a drug compound, the significance of watersolubility to pharmacokinetics cannot be underestimated. This isparticularly so when the absorption step for the compound is preceded bya dissolution step of the orally ingested dosage format. The in-vivodissolution step is often the rate determining step for drug absorption.Also, highly water-soluble drugs are, by the fact itself, less toxicthan lower water-soluble drugs due to their facilitated renal clearance.They will have a lesser tendency to accumulate in an organism thusavoiding overload to the liver.

Complex guanylhydrazones have been reported in the patent literatureabove. For instance, U.S. Pat. No. 5,599,984 to Bianchi et al. listedabove discloses hydrochloride salts of complex guanylhydrazone compoundswith some degree of water solubility. However, the high acidityassociated with some hydrochloride salts, upon dissociation, can causecellular damage and is a recognized source of phlebitis. Stranz et al.,Int. J. Pharm. Compounding (2002), v.6, n.3, pp. 216-220. Thus, there isa need in the art to develop salts of guanylhydrazone compounds, and inparticular salts of complex guanylhydrazone compounds, having both highwater solubility and lower probability of cellular insult due to theacidity of the salt upon dissociation in solution.

SUMMARY OF THE INVENTION

One embodiment of the present invention provides a pharmaceuticallyacceptable salt, comprising the following compound:

as a salt of at least one pharmaceutically acceptable acid selected fromthe group consisting of compounds having the following formulas:

wherein each C* independently represents a potentially chiral carbonthat can be in either the D or L enantiomeric configuration,

wherein each R is independently unsubstituted or substituted andselected from the group consisting of Y—, Y—O—, Y—S—, Y—SO₂—,(Y)₂—N—SO₂—, Y—(C═O)—, Y—(C═O)—O—, YO—(C═O)—, (Y)₂—N—, Y—(C═O)—(Y—N)—,(Y—(C═O))₂—N—, Y—(SO₂)—(Y—N)—, or (Y—(SO₂))₂—N—; each Y beingindependently selected from the group consisting of hydrogen, carboxyl,halo, hydroxyl, thiol, nitro, amine, NC—, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and(C₃-C₅)heterocyclic; wherein each of the aforesaid (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and(C₃-C₅)heterocyclic substituents may be substituted or unsubstituted;

wherein two independently chosen Y alkyl-containing groups may be takentogether with any nitrogen atom to which they are attached to form athree to twelve membered cyclic, heterocyclic or heteroaryl ring;

and wherein in the compound having the formula VII, L is a diradicalmoiety selected from the group consisting of (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol,(C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and(C₃-C₂₀)cycloalkyl; wherein each of the aforesaid (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol,(C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and(C₃-C₂₀)cycloalkyl diradical moieties may be substituted orunsubstituted.

Another embodiment of the invention provides a pharmaceuticallyacceptable salt, comprising one or more compounds having the formula:

wherein X¹, X², X³, and X⁴ each independently represent H, GhyCH—,GhyCCH₃—, or CH₃CO—, with the provisos that X¹, X², X³ and X⁴ are notsimultaneously H;

wherein Z is one or more selected from the group consisting of:

-(A¹)_(a)-(CR²R³)_(x)-(A²)_(b)-;

-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)_(y)-(A²)_(b)-; and

-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)_(y)-T_(n)-(CR⁶R⁷)_(z)-(A²)_(b)-;

and combinations thereof;

wherein a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein x is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein A¹ and A² are each independently selected from the groupconsisting of —NR⁸(CO)NR⁹—, —(CO)NR⁸, —NR⁸(CO)—, —NR⁸—, —O—, —S—,—S(═O)—, —SO₂—, —SO₂NR⁸, —NR⁸SO₂—, and salts thereof;

wherein Q and T are each independently selected from the groupconsisting of —NR¹⁰(CO)NR¹¹—, —(CO)NR¹⁰—, —NR¹⁰(CO)—, —NR⁸—, —O—, —S—,—S(═O), —SO₂—, —SO₂NR¹⁰—, —NR⁸SO₂—, salts thereof, branched orunbranched, saturated or unsaturated, substituted or unsubstitutedC₁-C₂₀ alkylene, saturated or unsaturated, substituted or unsubstitutedC₃-C₂₀ cycloalkylene, substituted or unsubstituted C₅-C₂₅ arylene, andcombinations thereof;

wherein one or more carbon atoms in any of said alkylene, cycloalkyleneor arylene in said Q and/or T may each be independently replaced withone or more heteroatoms selected from the group consisting of nitrogen,oxygen, sulfur, and a combination thereof;

and wherein when substituted, said alkylene, cycloalkylene or arylene insaid Q and/or T are each independently substituted with one or moresubstituent groups selected from the group consisting of hydroxy, halo,bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂,(C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₅)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O-1(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH-1perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {phenyl}N—C═O)—,{(C₂-C₂₀)alkenyl} {phenyl}N—C═O)—, {(C₃-C₂₀)cycloalkenyl}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₅)aryl}{phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O#,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀)cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

wherein each of the aforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, and (C₅-C₂₅)aryl groups (as substituents on saidalkylene, cycloalkylene or arylene of said Q and T) may be optionallyand independently substituted by one to four moieties selected from thegroup consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, —N₃,—CN, —NC, —SH, —NO₂, —NH₂, (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl,(C₁-C₂₀)alkyl-O—, phenyl-O—, (C₃-C₂₀)cycloalkyl-O—,(C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—, (C₂-C₂₀)alkenyl-O—,(C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—, (C₅-C₂₀)cycloalkynyl-O—,(C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—, (C₁-C₂₀)alkyl-S—, phenyl-S—,(C₃-C₂₀)cycloalkyl-S—, (C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—,(C₂-C₂₀)alkenyl-S—, (C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—,(C₅-C₂₀)cycloalkynyl-S—, (C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—,(C₁-C₂₀)alkyl-SO₂—, phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—,(C₁-C₂₀)alkoxy-SO₂—, (C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—S° 2-,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH-1 (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—,(C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O){((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O{-(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₋₅)heterocyclic}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₅)aryl} {(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl}{phenyl}N—(C═O)—, {(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—,{(C₃-C₂₀)heteroaryl} {phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₅)aryl} {phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—C═O)—,HO—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—,(C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—,(C₅-C₂₅)aryl-(C═O)—, perhalo(C₁-C₂₀)alkyl-(C═(O)—, phenyl-(C═O)—,(C₁-C₂₀)alkyl-O—(C═O)—, (C₃-C₂₅)heteroaryl-O—(C═O)—,(C₃-C₂₅)heterocyclic-O—(C═O)—, (C₂-C₂₀)alkenyl-O—(C═O)—,(C₃-C₂₀)cycloalkenyl-O—(C═O)—, (C₂-C₂₀)alkynyl-O—(C═O)—,(C₅-C₂₅)aryl-O—(C═O), perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—,(C₁-C₂₀)alkyl-(C═O)—O—, (C₃-C₂₅)heteroaryl-(C═O)—O—,(C₃-C₂₅)heterocyclic-(C═O)—O—, (C₂-C₂₀)alkenyl-(C═O)—O—,(C₃-C₂₀)cycloalkenyl-(C═O)—O—, (C₂-C₂₀)alkynyl-(C═O)—O—,(C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—, perhalo(C₁-C₂₀)alkyl-(C═O)—O—,and salts thereof; and

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected from the group consisting of hydrogen, hydroxy,halo, bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂,(C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH-1 phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH— (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—,{phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—,{(C₃-C₂₅)heteroaryl}₂N—, {(C₃-C₂₅)heterocyclic}₂N—,{(C₂-C₂₀)alkenyl}₂N—, {(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloakynyl-(C═O)—{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkoxy-(C═O){(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O){(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O){(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O){(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O{(phenyl)N}-, (C₅-C₂₅)aryl-(C═O){(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)alkoxy} {phenyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {phenyl)}N—C═O)—, {(C₂-C₂₀)alkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₅)aryl} {phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl}{phenyl}N—(C═O)—, HO—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—,(C₃-C₂₅)heteroaryl-(C═O)—, (C₃-C₂₅)heterocyclic-(C═O)—,(C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀) cycloalkenyl-(C═O)—,(C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₀)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

wherein each of the aforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀) cycloalkenyl, (C₂-C₂₀)alkynyl,(C₁-C₂₀)cycloalkynyl, and (C₅-C₂₅)aryl groups (for said R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ groups) may be optionally and independentlysubstituted by one to four moieties selected from the group consistingof hydroxy, halo, bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂,—NH₂, (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₋₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}N—SO₂—,{(C₁-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₋₅)heteroaryl-(C═O)NH—,(C₃-C₂₅)heterocyclic-(C═O)NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}—,(C₁-C₂₀)alkyloxy-(C═O)—{((C₁-C₂₀))alkyl)N}—, (C₃-C₂₅),heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O{-(phenyl)N}-,(C₂-C₂₀)alkenyl-(C-{-(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl} N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀))alkyl}N—(C═O)—, {(C₁-C₁₁))cycloalkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}-(C═O)—, {(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—,{(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—, {(C₂-C₂₀)alkenyl}{phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl} {phenyl)}N—(C═O)—,{(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl}{phenyl}N<C═O)—, {(C₅-C₂₅)aryl} {phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl}{phenyl}N—(C═O)—, HO—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—,(C₃-C₂₅)heteroaryl-(C═O)—, (C₃-C₂₅)heterocyclic-(C═O)—,(C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀) cycloalkenyl-(C═O)—,(C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₋₅)aryl-O—(C═O),perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

and wherein two independently chosen R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, and R¹¹ alkyl-containing groups may be taken together with any atomto which they are attached to form a three to forty membered cyclic,heterocyclic or heteroaryl ring;

as a salt of at least one pharmaceutically acceptable acid selected fromthe group consisting of compounds having the following formulas:

wherein each C* independently represents a potentially chiral carbonthat can be in either the D or L enantiomeric configuration;

wherein each R is independently unsubstituted or substituted andselected from the group consisting of Y—, Y—O—, Y—S—, Y—SO₂—,(Y)₂—N—SO₂—, Y—(C═O)—, Y—(C═O)—O—, YO—(C═O)—, (Y)₂—N—, Y—(C═O)—(Y—N)—,(Y—(C═O))₂—N—, Y—(SO₂)—(Y—N)—, or (Y—(SO₂))₂—N—; each Y beingindependently selected from the group consisting of hydrogen, carboxyl,halo, hydroxyl, thiol, nitro, amine, NC—, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and(C₃-C₅)heterocyclic; wherein each of the aforesaid (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and(C₃-C₅)heterocyclic substituents may be substituted or unsubstituted;

wherein two independently chosen Y alkyl-containing groups may be takentogether with any nitrogen atom to which they are attached to form athree to twelve membered cyclic, heterocyclic or heteroaryl ring;

and wherein in the compound having the formula VII, L is a diradicalmoiety selected from the group consisting of (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol,(C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and(C₃-C₂₀)cycloalkyl; wherein each of the aforesaid (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol.(C₃-C₂₀),aryl, (C₃-C₁₅)heteroaryl and (C₃-C₂₀)cycloalkyl diradicalmoieties may be substituted or unsubstituted.

Another embodiment of the invention provides a pharmaceuticallyacceptable composition, comprising the salt described above in contactwith at least one pharmaceutically acceptable carrier.

Another embodiment of the invention provides a method, comprisingadministering the salt or the pharmaceutically acceptable compositiondescribed above to a human.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that certain select acids form salts withguanylhydrazone compounds producing guanylhydrazone salts having anumber of advantages over known salts of guanylhydrazone compounds.These guanylhydrazone salts have been found to have an unexpectedlysuperior combination of formulation and solubility advantages which makethem particularly suitable for the preparation of pharmaceuticalformulations containing guanylhydrazone-containing drugs.

Thus, according to the present invention, there are provided improvedsalts of guanylhydrazone containing compounds. In a preferredembodiment, the inventive salts relate to salts of complexguanylhydrazone compounds (i.e., compounds that contain multipleguanylhydrazone moieties). In a most preferred embodiment, the complexguanylhydrazone compound is Semapimod:

The Semapimod compound (sometimes referred to herein as CNI-1493 isidentified as Compound No. 14 in U.S. Pat. No. 5,599,984 to Bianchi etal., the entire contents of which are hereby incorporated by reference.

The invention also relates to alternative pharmaceutical dosage formatsinvolving the guanylhydrazone salts of the invention. The alternativeformats include, for example, hard gelatin capsules or quick releasetablets for oral consumption, compositions for topical application, orvarious solutions for parenteral injection (including, but not limitedto subcutaneous and intramuscular) or infusion. In addition, theguanylhydrazone salts of the invention provide improved storagecapabilities for the active agent compound in an improved stable format.

Other aspects of the invention relate to methods of making theguanylhydrazone salts according to the invention.

Other aspects of the invention relate to methods of using the inventiveguanylhydrazone salts in various applications such as screening assays,efficacy and safety tests, and in therapies or treatments. These methodsof use involve, among other things, in vitro testing and in vivotesting. The inventive guanylhydrazone salts can also be used intherapeutic methods for which a guanylhydrazone compound has previouslybeen identified as effective as the active agent, but which heretoforehave not been identified in an improved salt form for enhanced deliveryand bioavailability.

According to one embodiment, a guanylhydrazone salt according to theinvention includes one or more guanylhydrazone compounds combined with acarboxylic acid. One suitable carboxylic acid for the salt combinationincludes a chemical structure having one of the following formulas (Iand II):

In the carboxylic acid formulas I and II above, C* represents apotentially chiral carbon that can be in either the D or L enantiomericconfiguration, and R represents a suitable substituent such as, but notlimited to, hydrogen (H), or methyl (CH₃) or other alkyl. The “0-20”range includes all values and subranges therebetween, including 0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

More particularly, in the carboxylic acid formulas I and II above, eachR may be independently selected from Y—, Y—O—, Y—S—, Y—SO₂—,(Y)₂—N—SO₂—, Y—(C═O), Y—(C═O)—O—, YO—(C═O)—, (Y)₂—N—, Y—(C═O)—(Y—N)—,(Y—(C═O))₂—N—, Y—(SO₂)—(Y—N)—, or (Y—(SO₂))₂—N—; wherein twoindependently chosen Y alkyl-containing groups may be taken togetherwith any nitrogen atom to which they are attached to form a three totwelve membered cyclic, heterocyclic or heteroaryl ring, and each Y isindependently selected from hydrogen, carboxyl, halo, hydroxyl, thiol,nitro, amine, NC—, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy,(C₅-C₇)aryl, (C₃-C₅)heteroaryl, and (C₃-C₅)heterocyclic; wherein each ofthe aforesaid (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy,(C₅-C₇)aryl, (C₃-C₅)heteroaryl, and (C₃-C₅)heterocyclic substituents mayoptionally be substituted with one or more suitable substituentsdescribed herein, as in for instance a halo-substituted alkyl, by one toten moieties independently selected from the group consisting ofcarboxyl, halo, hydroxyl, thiol, nitro, amine, NC—, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₂-C₄)alkenyl, and (C₂-C₄)alkynyl.

According to another embodiment, the carboxylic acid in theguanylhydrazone salt is described by the following general formula(III):

wherein C* and each R, independently, are defined as described for thecarboxylic acid formulas I and II above. In one aspect of thisembodiment the carboxylic acid is acetic acid:

According to another embodiment, the carboxylic acid in theguanylhydrazone salt according to the invention is described by thefollowing general formula (IV):

wherein C* and R are defined as described for the carboxylic acidformulas I and II above. In one aspect of this embodiment the carboxylicacid is L-lactic acid:

According to another embodiment, the carboxylic acid in theguanylhydrazone salt according to the invention is described by thefollowing general formula (V):

wherein C* and R are defined as described for the carboxylic acidformulas I and II above. In one aspect of this embodiment the carboxylicacid is L-Aspartic Acid:

According to another embodiment, the carboxylic acid in theguanylhydrazone salt according to the invention is described by thefollowing general formula (VI):

wherein C* and R are defined as described for the carboxylic acidformulas I and II above. In one aspect of this embodiment the carboxylicacid is L-glutamic acid:

According to another embodiment the guanylhydrazone-carboxylic acidsalts according to the invention include a guanylhydrazone compoundcombined with a carboxylic acid wherein a suitable carboxylic acid forthe salt combination, according to this embodiment, is a chemicalstructure described by the following general formula (VII):

wherein L is a diradical moiety selected from a (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol,(C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and(C₃-C₂₀)cycloalkyl; wherein each of the aforesaid (C₁-C₂₀)alkyl,(C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol,(C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and(C₃-C₂₀)cycloalkyl diradical moieties may optionally be substituted, forexample, with one or more suitable substituents defined herein, forexample a halo-substituted alkyl, by one to twenty moietiesindependently selected from the group including carboxyl, halo,hydroxyl, thiol, nitro, amine, Y or R wherein these terms are definedherein.

According to another embodiment, the anion for the guanylhydrazone saltmay be described by one of the following general formulas:

wherein C* and R represent suitable substituents as defined herein. Themonovalent form of the above divalent anion is also suitable.

In another embodiment, the acid form of the guanylhydrazone salt mayhave one of the following formulas:

Either the monovalent or divalent anion forms of the acids are suitable.

According to another embodiment, the anion in the guanylhydrazone saltaccording to the invention is described by the following generalformula:

In one aspect of this embodiment, the anion is mesylate.

Of course, the acid form of the above anion may be described as follows:

In the compounds herein, a “suitable substituent” is intended to mean afunctional group that does not negate the intended activity of theactive guanylhydrazone compound in the salt. For example, the suitablesubstituent would not negate the activity of the guanylhydrazonecompound. Illustrative examples of suitable substituents include, butare not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxygroups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups,oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl orheteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO—(C═O)—groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups,dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonylgroups, alkylsulfonyl groups, arylsulfonyl groups and the like.Combinations of substituents are possible.

As used herein, the term, “alkylene” refers to a diradical alkanespecies that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 and 20 carbons or any subrange of carbons therebetween.The alkylene may be branched or unbranched, saturated or unsaturated,and substituted or unsubstituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl. In addition, any carbon atom therein may be optionallyreplaced with one or more heteroatoms such as nitrogen, oxygen or sulfuror any combination thereof.

As used herein, the term, “cycloalkylene” refers to a diradicalcycloalkane species that contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19 and 20 ring carbons or any subrange of carbonstherebetween. The cycloalkylene may be branched or unbranched, saturatedor unsaturated. and substituted or unsubstituted with one or moresuitable substituents defined herein, for example with one or morefluoro, chloro, trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy,difluoromethoxy or (C₁-C₃)alkyl. In addition, any carbon atom thereinmay be optionally replaced with one or more heteroatom such as nitrogen,oxygen or sulfur or any combination thereof.

As used herein, the term “arylene” means an aromatic diradical specieshaving 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24 and 25 carbons and any subrange of carbons thereof. These maybe unsubstituted or substituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl. In addition, any carbon atom therein may be optionallyreplaced with one or more heteroatom such as nitrogen, oxygen or sulfuror any combination thereof to form a heteroarylene.

As used herein, the term “alkyl” as well as the alkyl moieties of orwithin other groups referred to herein (e.g., (C₁-C₂₀)alkyl,(C₁-C₂₀)alkoxy, (C₂-C₂₀)alkenyl, (C₂-C₂₀)alkynyl, andperhalo(C₁-C₂₀)alkyl) include alkyl moieties having 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons or anysubrange of carbons therebetween. They may be linear or branched (suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl, etc.). They may be saturated orunsaturated as indicated by the “alkenyl” or “alkynyl” terminology.Other than the perhaloalkyl, which are completely substituted by one ormore of the same or different halogens, the alkyl groups may beunsubstituted or substituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl.(C₁-C₃)alkoxy. trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl.

As used herein, the term “cycloalkyl” as well as the other moietieshaving cyclic groups referred to herein (for example (C₃-C₂₀)cycloalkyl,(C₃-C₂₀)cycloalkenyl and (C₅-C₂₀)cycloalkynyl) refers to monocarbocyclic moieties having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 and 20 ring carbons or any subrange of carbonstherebetween. They may be unsubstituted or substituted with one or moresuitable substituents defined herein, for example with one or morefluoro, chloro, trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy,difluoromethoxy or (C₁-C₃)alkyl.

As used herein, the terms, “alkenyl,” “alkynyl,” “cycloalkynyl,” and“cycloalkenyl” refer to unsaturated radical species having 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons(or, for the cyclic species 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 and 20 ring carbons) or any subrange of carbons or ringcarbons therebetween. They may be branched or unbranched, and they maybe unsubstituted or substituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl. These groups have one or more than one site ofunsaturation, i.e., one or more double or triple bonds. For example,these moieties may have one, two, three, four or more sites ofunsaturation. Some nonlimiting examples of these include ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and2-butynyl.

As used herein, the term, “alkoxy” refers to alkyl-O— radical specieshaving 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19and 20 carbons or any subrange of carbons therebetween. They may beunsubstituted or substituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl.

As used herein, the term “halogen” or “halo” includes fluoro, chloro,bromo or iodo, and any combination thereof.

As used herein, the term “aryl” means aromatic radicals having 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and25-carbons and any subrange of carbons thereof. These may beunsubstituted or substituted with one or more suitable substituentsdefined herein, for example with one or more fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl. Nonlimiting examples include phenyl, naphthyl,tetrahydronaphthyl, indanyl and the like.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup with at least one heteroatom selected from O, S and N in the ringand having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24 and 25 ring carbons and any subrange of carbonsthereof. The heteroatoms may be present either alone or in anycombination. The heteroaryl groups may be unsubstituted or substitutedwith one or more suitable substituents defined herein, for example withone or more fluoro, chloro, trifluoromethyl, (C₁-C₃)alkoxy,trifluoromethoxy, difluoromethoxy or (C₁-C₃)alkyl. One, two, three, fouror more heteroatoms may be present. In addition to the heteroatom, thearomatic group may optionally have up to four N atoms in the ring.Nonlimiting examples of heteroaryl groups include pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl(e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl,1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl,benzofuryl, indolyl, and the like; which are optionally unsubstituted orsubstituted with one or more suitable substituents defined herein, forexample with one or more fluoro, chloro, trifluoromethyl, (C₁-C₃)alkoxy,trifluoromethoxy, difluoromethoxy or (C₁-C₃)alkyl.

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24 and 25 ring carbons and any subrange of carbonsthereof carbon atoms and hetero atoms selected from N, O, S or NR′.Nonlimiting examples include azetidinyl, tetrahydrofuranyl,imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl,thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl,chromanyl, isochromanyl, benzoxazinyl and the like. Examples of suchmonocyclic saturated or partially saturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; which may be unsubstituted oroptionally substituted with one or more suitable substituents definedherein, for example with one or more fluoro, chloro, trifluoromethyl,(C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or (C₁-C₃)alkyl. R¹ canbe any suitable substituent, for example Y as defined herein, or morepreferably methyl.

As used herein, the term “halo-substituted alkyl” refers to an alkylradical as described above substituted with one or more halogensincluding, but not limited to, chloromethyl, dichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, andthe like; optionally further substituted with one or more suitablesubstituents defined herein, for example fluoro, chloro,trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy, difluoromethoxy or(C₁-C₃)alkyl.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl-(C═O)— or alkoxycarbonyl) refers to the joinderof the C═O moiety to a second moiety such as an alkyl or amino group(i.e., an amido group). Alkoxycarbonylamino (i.e., alkoxy(C═O)—NH—)refers to an alkyl carbamate group. The carbonyl group is alsoequivalently defined herein as (C═O). Alkylcarbonylamino refers togroups such as acetamide.

One preferred embodiment of this invention is a salt wherein aguanylhydrazone compound is combined with L-Lactic Acid. In a morepreferred embodiment, the salt is guanylhydrazone compound containingmultiple guanylhydrazone moieties and combined with L-Lactic Acid. In amost preferred embodiment, the invention relates to a salt combining theguanylhydrazone-containing compound with L-Lactic Acid.

In another embodiment, the invention relates to a guanylhydrazonecompound, for example Semapimod, combined with other acids to form apharmaceutically acceptable salt. The acids which are used to preparethe pharmaceutically acceptable acid addition salts of theguanylhydrazone compounds invention include those which form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the chloride, bromide, iodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, diphosphate, citrate, acidcitrate, tartrate, bitartrate, succinate, fumarate, tosylate, mesylate,gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)), bicarbonate, edetate,camsylate, carbonate, dihydrochloride, edentate, edisylate, estolate,esylate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, mandelate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, pantothenate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, teoclate, and triethiodide salts.Mixtures of salts are possible.

Any ratio of guanylhydrazone:counterion in the salt form, for example,guanylhydrazone:counterion ratios of 10, 9, 8, 7, 6, 5, 4, 3, 2, 1:1, 2,3, 4, 5, 6, 7, 8, 9, 10 is suitable. The ratio can be expressed as thenumber of “Ghy” groups counterions or as the number of ionicguanylhydrazone molecules:counterions as appropriate. In one embodiment,either the guanylhydrazone or the counterion or both may be multivalent,and the ratio is adjusted accordingly such that the salt may adopt azero or non-zero charge. Mixed salts are possible.

Other suitable salts include those of the guanylhydrazone compoundshaving the formula:

wherein X¹, X², X³, and X⁴ each independently represent H, GhyCH—,GhyCCH₃—, or CH₃CO-1 with the provisos that X¹, X², X³ and X⁴ are notsimultaneously H;

wherein Z is one or more selected from the group consisting of:

-(A¹)_(a)-(CR²R³)_(x)-(A²)_(b)-;

-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)-(A²)_(b)-; and

-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)_(y)-T_(n)-(CR⁶R⁷)_(z)-(A²)_(b);

and combinations thereof;

wherein a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein x is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein m is selected from the group consisting of 0, 2, 3, 4, 5, 6, 7,8, and 9;

wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8, and 9;

wherein A¹ and A² are each independently selected from the groupconsisting of —NR⁸(CO)NR⁹—, —(CO)NR⁸—, —NR⁸(CO)—, —NR⁸—, —O—, —S—,—S(═O)—, —SO₂—, —SO₂NR⁸—, —NR⁸SO₂—, and salts thereof;

wherein Q and T are each independently selected from the groupconsisting of —NR¹⁰(CO)NR¹¹—, —(CO)NR¹⁰—, —NR¹⁰(CO—, NR¹⁰—, —O—, —S—,—S(═O)—, —SO₂—, —SO₂NR¹⁰—, —NR¹⁰SO₂—, salts thereof, branched orunbranched, saturated or unsaturated, substituted or unsubstitutedC₁-C₂₀ alkylene, saturated or unsaturated, substituted or unsubstitutedC₃-C₂₀ cycloalkylene, substituted or unsubstituted C₁-C₂₅ arylene, andcombinations thereof;

wherein one or more carbon atoms in any of said alkylene, cycloalkyleneor arylene in said Q and/or T may each be independently replaced withone or more heteroatoms selected from the group consisting of nitrogen,oxygen, sulfur, and a combination thereof;

and wherein when substituted, said alkylene, cycloalkylene or arylene insaid Q and/or T are each independently substituted with one or moresubstituent groups selected from the group consisting of hydroxy, halo,bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂,(C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀) cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₃-C₂₀)cycloalkyl-SO₂—SO₂,(C₁-C₂₀)alkoxy-SO₂—NH—,(C₃-C₂₀)heteroaryl-SO, —NH—, (C₃-C₂₅)heterocyclic-SO₂—NH—,(C₂-C₂₀)alkenyl-SO₂—NH—, (C₃-C₂₀)cycloalkenyl-SO₂—NH—,(C₂-C₂₀)alkynyl-SO₂—NH—, (C₅-C₂₀)cycloalkynyl-SO₂—NH—,(C₅-C₂₅)aryl-SO₂—NH—, perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—,phenyl-NH—, (C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—,(C₃-C₂₅)heteroaryl-NH—, (C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—,(C₃-C₂₀)cycloalkenyl-NH—, (C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—,(C₅-C₂₅)aryl-NH—, perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—,{phenyl}₂N—, {(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—,{(C₃-C₂₅)heteroaryl}₂N—, {(C₃-C₂₅)heterocyclic}₂N—,{(C₂-C₂₀)alkenyl}₂N—, {(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O—NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₁₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O{-(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O{(phenyl)N}-, (C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₋₅)heterocyclic}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₅)aryl} {(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl}{phenyl}N—(C═O)—, {(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—, {(C₃-C₂₀)heterocyclic}{phenyl}N—(C═O), {(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₅)aryl} {phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl)}{phenyl}N—(C═O)—, HO—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—,(C₃-C₂₅)heteroaryl-(C═O)—, (C₃-C₂₅)heterocyclic-(C═O)—,(C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀) cycloalkenyl-(C═O)—,(C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₀)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

wherein each of the aforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀) cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, and (C₅-C₂₅)aryl groups (as substituents on saidalkylene, cycloalkylene or arylene of said Q and T) may be optionallyand independently substituted by one to four moieties selected from thegroup consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, —N₃,—CN, —NC, —SH, —NO₂, —NH₂, (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀) cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl,(C₁-C₂₀)alkyl-O—, phenyl-O—, (C₃-C₂₀)cycloalkyl-O—,(C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—, (C₂-C₂₀)alkenyl-O—,(C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—, (C₅-C₂₀)cycloalkynyl-O—,(C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—, (C₁-C₂₀)alkyl-S—, phenyl-S—,(C₃-C₂₀)cycloalkyl-S—, (C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—,(C₂-C₂₀)alkenyl-S—, (C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—,(C₅-C₂₀)cycloalkynyl-S—, (C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—,(C₁-C₂₀)alkyl-SO₂—, phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—,(C₁-C₂₀)alkoxy-SO₂—, (C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, (C₂-C₂₀)alkenyl)₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₋₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-,phenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)—{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O){(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O#{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)—{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N-(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl)}N—(C═O)—,{(C₃-C₂₅)heteroaryl}{phenyl}N—(C═O)-, {(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₅)aryl}{phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O)—,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₋₅)aryl-O—(C═O),perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof; and

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected from the group consisting of hydrogen, hydroxy,halo, bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂,(C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀) cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)NH—, (C₂-C₂₀)alkenyl-(C═O)NH—,(C₃-C₂₀)cycloalkenyl-(C═O)NH—, (C₂-C₂₀)alkynyl-(C═O)NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)NH—, (C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₁₁)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O){((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)—{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)—{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O){((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O){(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}—,(C₂-C₂₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O){(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O), (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl)}-(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl)}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N+C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₅)aryl}{phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O)—,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

wherein each of the aforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀) cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, and (C₅-C₂₅)aryl groups (for said R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ groups) may be optionally and independentlysubstituted by one to four moieties selected from the group consistingof hydroxy, halo, bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂,—NH₂, (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl,(C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—S₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—N—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₁₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₁-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)—{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O#{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-, (C₅-C₂₅)aryl-(C═O){(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O), (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, —{(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O), {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)-, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₅)aryl}{phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═(O)—,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₁-C₂₀)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₅-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof;

and wherein two independently chosen R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, and R¹¹ alkyl-containing groups may be taken together with any atomto which they are attached to form a three to forty membered cyclic,heterocyclic or heteroaryl ring.

In the present application, “Ghy” is a guanylhydrazone group; GhyCH— isNH₂C(═NH)—NH—N—CH—; and GhyCH₃— is NH₂C(═NH)—NH—N═CCH₃—.

In another embodiment, a pharmaceutical composition of the carboxylicacid salt of the guanylhydrazone compound together with apharmaceutically acceptable diluent or carrier is provided.

The invention further provides a tablet formulation comprising thecarboxylic acid salt of the guanylhydrazone compound in an admixturewith excipients. One embodiment formulation includes the carboxylic acidsalt of the guanylhydrazone compound, a compression aid such asmicrocrystalline cellulose, an additive to provide sheen to the tablesuch as anhydrous dibasic calcium phosphate, a disintegrant such assodium starch glycolate and a lubricant such as magnesium stearate.

In addition the invention provides a capsule formulation comprising thecarboxylic acid salt of the guanylhydrazone compound in an admixturewith excipients. A preferred formulation includes the salt, an inertdiluent, a dried disintegrant and a lubricant as described above.

The invention further provides the carboxylic acid salt of theguanylhydrazone compound in sterile aqueous solution for parenteraladministration. Preferably such solution contains from 10 to 40% byvolume of propylene glycol and preferably also sufficient sodiumchloride to avoid haemolysis, e.g. about 1% w/v. The invention alsoprovides the carboxylic acid salt of the guanylhydrazone compound foruse in treating diseases and conditions as described in the patents andpatent application publications listed above.

The guanylhydrazone compounds and certain carboxylic acids incombination thereof in the present invention can exist in severaltautomeric forms, and geometric isomers and mixtures thereof. All suchtautomeric forms are included within the scope of the present invention.Tautomers exist as mixtures of tautomers in solution. In solid form,usually one tautomer predominates. Even though one tautomer may bedescribed, the present invention includes all tautomers of the presentcompounds.

The salt structures formed can be in either mono, di, tri, tetra orother salt structures and combinations thereof. The present inventionalso includes atropisomers of the present invention. Atropisomers referto compounds of the invention that can be separated into rotationallyrestricted isomers. The compounds of this invention may containolefin-like double bonds. When such bonds are present, the compounds ofthe invention exist as cis and trans configurations and as mixturesthereof.

The present invention also includes isotopically-labeled acid compounds,which are identical to those recited above, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ¹⁸F, and ³⁶Cl, respectively. Compounds of the presentinvention, prodrugs thereof, and pharmaceutically acceptable salts ofsaid compounds or of said prodrugs which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, would be preferredin some circumstances. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed herein by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

In other embodiments, the invention relates to a guanylhydrazonecompound combined with one or more acids, such as carboxylic acid, orone or more anions, such as mesylate, to form a salt having a solubilityin pure water of at least 0.001 mg/mL, more preferably 0.01 mg/mL, morepreferably 0.1 mg/mL, more preferably 0.2 mg/mL, more preferably 0.3mg/mL, more preferably 0.4 mg/mL, more preferably 0.5 mg/mL, morepreferably 0.7 mg/mL, more preferably 1 mg/mL, more preferably 2 mg/mL,more preferably 3 mg/mL, more preferably 4 mg/mL, more preferably 5mg/mL, more preferably 10 mg/mL, more preferably 20 mg/mL, even morepreferably 30 mg/mL, still more preferably 40 mg/mL, yet still morepreferably 50 mg/mL, more preferably 55 mg/mL, more preferably 75 mg/mL,more preferably 85 mg/mL, more preferably 100 mg/mL, more preferably 200mg/mL, more preferably 300 mg/mL, more preferably 500 mg/mL and mostpreferably 1000 mg/mL.

In other embodiments, the invention relates to a guanylhydrazonecompound combined with one or more acids or anions to form a salt havinga solubility, in a 5% by weight dextrose aqueous solution with purewater, of at least 0.001 mg/mL, more preferably 0.01 mg/mL, morepreferably 0.1 mg/mL, more preferably 0.2 mg/mL, more preferably 0.3mg/mL, more preferably 0.4 mg/mL, more preferably 0.5 mg/mL, morepreferably 0.7 mg/mL, more preferably 1 mg/mL, more preferably 2 mg/mL,more preferably 3 mg/mL, more preferably 4 mg/mL, more preferably 5mg/mL, more preferably 10 mg/mL, more preferably 20 mg/mL, even morepreferably 30 mg/mL, still more preferably 40 mg/mL, yet still morepreferably 50 mg/mL, more preferably 55 mg/mL, more preferably 75 mg/mL,more preferably 85 mg/mL, more preferably 100 mg/mL, more preferably 200mg/mL, more preferably 300 mg/mL, more preferably 500 mg/mL and mostpreferably 1000 mg/mL.

In other embodiments, the invention relates to a guanylhydrazonecompound combined with one or more acids or anions to form a salt havinga solubility, in both pure water and in a 5% by weight dextrose aqueoussolution with pure water, of at least 0.001 mg/mL, more preferably 0.01mg/mL, more preferably 0.1 mg/mL, more preferably 0.2 mg/mL, morepreferably 0.3 mg/mL, more preferably 0.4 mg/mL, more preferably 0.5mg/mL, more preferably 0.7 mg/mL, more preferably 1 mg/mL, morepreferably 2 mg/mL, more preferably 3 mg/mL, more preferably 4 mg/mL,more preferably 5 mg/mL, more preferably 10 mg/mL, more preferably 20mg/mL, even more preferably 30 mg/mL, still more preferably 40 mg/mL,yet still more preferably 50 mg/mL, more preferably 55 mg/mL, morepreferably 75 mg/mL, more preferably 85 mg/mL, more preferably 100mg/mL, more preferably 200 mg/mL, more preferably 300 mg/mL, morepreferably 500 mg/mL and most preferably 1000 mg/mL.

In one embodiment, the salt is made with L-Lactic Acid and Semapimod.

In another embodiment, the salt is Semapimod with mesylate anion.

One embodiment of the present invention relates to pharmaceuticalcompositions comprising one or more pharmaceutically acceptable saltsand one or more a pharmaceutically acceptable carrier, excipient,adjuvant and/or diluent. Other embodiments relate to methods of makingand using the salts, for example wherein the salt is used to assay ortest the guanylhydrazone compound or methods of use in which theguanylhydrazone compound is the active principle in a known therapyusing that active principle.

The salts may be suitably prepared according to known methods, forexample, by contacting the free base form of the guanylhydrazonecontaining compound with a sufficient amount of the desired acid toproduce a salt in the conventional manner.

The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide, potassium carbonate, ammonia and sodium bicarbonate. The freebase forms differ from their corresponding salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe salts are otherwise equivalent to their corresponding free baseforms for purposes of this invention.

The salts cam be administered in combination with one or moresubstantially nontoxic pharmaceutically acceptable carriers, excipients,adjuvants or diluents. The compositions of the present invention may beprepared in any conventional solid or liquid carrier or diluent andoptionally any conventional pharmaceutically-made adjuvant at suitabledosage level in a known way. The preferred preparations are inadministrable form which is suitable for oral application. Theseadministrable forms, for example, include pills, tablets, film tablets,coated tablets, capsules, powders and deposits.

Forms other than orally administrable forms are also possible. Thecompounds of the present invention and/or pharmaceutical preparationscontaining said compounds may be administered by any appropriate means,including but not limited to injection (intravenous, intraperitoneal,intramuscular, subcutaneous) by absorption through epithelial ormucocutaneous linings (oral mucosa, rectal and vaginal epitheliallinings, nasopharyngeal mucosa, intestinal mucosa); orally, rectally,transdermally, topically, intradermally, intragastrally, intracutanly,intravaginally, intravasally, intranasally, intrabuccally, percutanly,sublingually, or any other means available within the pharmaceuticalarts.

The pharmaceutically acceptable carrier may be suitably selected withrespect to the intended form of administration, i.e. oral tablets.capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the salt may be combined with any oralnontoxic pharmaceutically acceptable inert carrier, such as lactose,starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate,calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and thelike. Moreover, when desired or needed, suitable binders, lubricants,disintegrating agents and coloring agents may also be incorporated inthe mixture. Powders and tablets may be comprised of from about 5 toabout 95 percent by weight of the inventive compound, salt thereof, or amixture of compound and salt, which range includes all values andsubranges therebetween, including 10, 15, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, and 90% by weight.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethyl-cellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compounds or compositions of the present invention maybe formulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. antihistaminic activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of various disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.Nonlimiting examples include water, ethanol, ethanolic, water-ethanol orwater-propylene glycol solutions for parenteral injections or additionof sweeteners and opacifiers for oral solutions, suspensions andemulsions. Liquid form preparations may also include solutions forintranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the present invention may also be deliverabletransdermally. The transdermal compositions may take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

The term capsule refers to a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

Tablet means compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction well known to a person skilled in the art.

Oral gels refers to the active ingredients dispersed or solubilized in ahydrophillic semi-solid matrix.

Powders for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

Suitable diluents are substances that usually make up the major portionof the composition or dosage form.

Suitable diluents include sugars such as lactose, sucrose, mannitol andsorbitol, starches derived from wheat, corn rice and potato, andcelluloses such as microcrystalline cellulose. The amount of diluent inthe composition can range from about 5 to about 95% by weight of thetotal composition, preferably from about 25 to about 75%, morepreferably from about 30 to about 60% by weight.

The term disintegrants refers to materials added to the composition tohelp it break apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches, “cold water soluble” modified starchessuch as sodium carboxymethyl starch, natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar, cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose,microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose, alginates such as alginic acid and sodiumalginate, clays such as bentonites, and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 20% by weight of the composition, more preferably from about 5 toabout 10% by weight.

Binders characterize substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose, starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropyl-methylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

Lubricant refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d,l-leucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.2 to about 5% by weight of thecomposition, preferably from about 0.5 to about 2%, more preferably fromabout 0.3 to about 1.5% by weight.

Glidents are materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

Other techniques for formulation and administration may be found in“Remington's Pharmaceutical Sciences” Mack Publishing Co., Easton Pa.,the entire contents of which are hereby incorporated by reference. Asuitable composition comprising at least one compound of the inventionmay be a solution of the compound in a suitable liquid pharmaceuticalcarrier or any other formulation such as tablets, pills, film tablets,coated tablets, dragees, capsules, powders and deposits, gels, syrups,slurries, suspensions, emulsions, and the like.

The term “treating” as used herein refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich the term applies, or one or more symptoms of the disorder orcondition. The term “treatment” as used herein refers to the act oftreating as the term is defined above.

The compound of the present invention may exist in any convenientcrystalline, semicrystalline, or amorphous form. These may be achievedvia typical crystallization routes including vacuum crystallization orspray drying. Depending on the solubility desired, the amorphous formobtained by, e.g., spray-drying may be preferred. The spray drying maybe carried out from aqueous, ethanolic, organic, or mixed aqueousethanolic solutions of the salt or a mixture of the salt and the freebase compound. The compound and/or salt may exist in a form comprisingone or more waters of hydration.

The guanylhydrazone compound is suitably administered in the form of asalt of a pharmaceutically acceptable acid. The pharmaceuticallyacceptable salt desirably satisfies one or more of the followingphysiochemical criteria: (1) good solubility; (2) good stability; (3)non-hydroscopicity; (4) processability for oral, parenteral, or topicalformulations, etc. A range of pharmaceutically acceptableguanylhydrazone salts have been made and evaluated using these criteria.

The present salts desirably have good aqueous solubility and goodbioavailability. Usually a solubility of greater than 1 mg/mL at pH1-7.5 is sought although higher solubilities are required to formulateinjections. In addition, salts which provide solutions having a pH closeto that of blood (7.4) are preferred because they are readilybiocompatible and can easily be buffered to the required pH rangewithout altering their solubility. The L-lactate salt of Semapimodexhibits very good solubility.

Good stability in the solid state is desirable for tablets and capsules,while good stability in solution is required for an aqueous injection.In the case of tablets the vehicle can be comprised of, for instance,microcrystalline cellulose in 50:50 combination with anhydrous dibasiccalcium phosphate. In the case of capsules the vehicles can be comprisedof, for instance, mannitol in 4:1 combination with dried maize starch.In order to provide stable formulations it is desirable to have anon-hygroscopic salt. In the solid state where drug content is high,absorbed films of moisture can act as a vector for hydrolysis andchemical breakdown. It is the hygroscopic nature of a drug or its saltwhich contributes to the free moisture which is normally responsible forinstability.

The present salts are desirably easily processed, i.e. they have goodcompression properties and also the ability not to stick or adhere tothe tablet making machinery. For high dose formulations, goodcompressibility is desirable in terms of making elegant tablets. Withlower dose tablets the need for good compressibility can be eliminatedto a certain extent by the use of suitable diluting excipients calledcompression aids. Microcrystalline cellulose is a commonly usedcompression aid.

EXAMPLES

In order that the present invention be more readily understood,reference is now made to the following Examples, which are not intendedto be limiting unless otherwise indicated.

Example 1 Procedure for Semapimod Free Base Preparation

An AG1-X8 resin from Bio-Rad (20-50 mesh, hydroxide form, 20 g) wasswished in 100 mL of 1 N NaOH solution at room temp. for about 5minutes, and was filtered. The resin was then rinsed with 100 mL of H₂O,followed by 200 mL of MeOH. The resin was then added to 50 mL of a MeOHsolution containing 2 g of the Semapimod-4 HCl salt. The mixture wasthen stirred at room temp. for 60 min, and then filtered.

The resin was rinsed with about 50 mL of MeOH. The combined filtrate wasconcentrated under reduced pressure to afford 1.72 g of a light yellowsolid. HPLC analysis of the product showed 98.9% purity. The productprepared from the same procedure was subjected to elemental analysis,and the results showed a closer match to Semapimod-4H₂O. ¹H NMR of theproduct showed the same pattern of spectrum as the starting material,but with the signals from the methyl group and the aromatic hydrogenslightly shifted up-field. Recovery from this process was usually morethan 95%.

Example 2 Solubility of Semapimod-2 HCl/4H₂O

The product isolated as Semapimod-2 HCl/4H2O was added to ca. 2 mL ofsolvents (H₂O, 5% Dextrose solution, PBS, and 0.9% NaCl solution), andwas sonicated at room temperature until the solid suspended in thesolution. The mixture was passed through a Nylon syringe filter, andthen 0.5 mL of the filtrate was diluted with MeOH before injection intothe HPLC. The concentration of Semapimod-2 HCl/4H₂O in the filtrate wascalculated by comparing the results with a standard solution preparedfrom Semapimod-4 HCl/4H₂O. For reference purpose, the solubility ofSemapimod-4 HCl/4H₂O was determined according to the previous procedure.

The solubility of Semapimod-2 HCl/4H₂O was examined and is listed below:

H₂O: ca. 9.54 mg/mL5% Dextrose: 13.44 mg/mL

PBS: 0

0.9% NaCl soln: 0The solubility of Semapimod-4 HCl/4H₂OH₂O: 14.15 mg/mL

Example 3 Preparation of Semapimod (CNI-1493) Salts

The following Semapimod salts were prepared according to the proceduredescribed above. The results are summarized in the following Table:

TABLE I Salts Filtration Form acetate easy white solid L-glutamatemedium white solid L-lactate easy white solid mesylate medium¹ whitesolid sulfate easy white solid ¹Product was tacky and adhered to thereaction vessel.

The Semapimod sulfate precipitated out of the solution as a white solid,and the isolated product was not soluble in DMSO-d6, methanol-d4, or D2.

Example 4 Solubility Testing

The Semapimod salts mentioned in the above table were subjected tosolubility tests using the same procedure outlined above. The resultswere compared to a standard solution prepared from Semapimod-4 HCl/4H₂Oto determine the concentration of the salts in either H₂O or 5% dextrosesolution. The results are listed in the following table:

TABLE II Solubility in 5% Solubility in H₂O¹, dextrose solution, Salts(mg/mL)² (mg/mL)² acetate 43.3 18.1 L-glutamate ≧51.8 ≧42.7 L-lactate≧59.2 ≧49.9 mesylate 35.4 ≧46.4 sulfate 0 0 ¹H₂O was from Pharmco, HPLCgrade, and was used without further modification. ²The molecular weightof each salt was assumed 900 to get the approximate readings in mg/mL.

For Semapimod glutamate and lactate, both salts appeared to be solublefreely in H₂O and 5% dextrose solution. To conserve the products,solutions less than saturation used in the solubility test.

It will be recognized by those skilled in the art that changes can bemade to the embodiments of the invention without departing from thebroad inventive concepts thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but isintended to cover all modifications which are within the spirit andscope of the invention.

1. A pharmaceutically acceptable salt, comprising the followingcompound:

as a salt of at least one pharmaceutically acceptable acid selected fromthe group consisting of compounds having the following formulas:

wherein each C* independently represents a potentially chiral carbonthat can be in either the D or L enantiomeric configuration, whereineach R is independently unsubstituted or substituted and selected fromthe group consisting of Y—, Y—O—, Y—S—, Y—SO₂—, (Y)₂—N—SO₂—, Y—(C═O)—,Y—(C═O)—O—, YO—(C═O)—, (Y)₂—N—, Y—(C═O)—(Y—N)—, (Y—(C═O))₂—N—,Y—(SO₂)—(Y—N)—, or (Y—(SO₂))₂—N—; each Y being independently selectedfrom the group consisting of hydrogen. carboxyl. halo, hydroxyl, thiol,nitro, amine, NC—, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy,(C₅-C₇)aryl, (C₃-C₅)heteroaryl, and (C₃-C₅)heterocyclic; wherein each ofthe aforesaid (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy,(C₅-C₇)aryl, (C₃-C₅)heteroaryl, and (C₃-C₅)heterocyclic substituents maybe substituted or unsubstituted; wherein two independently chosen Yalkyl-containing groups may be taken together with any nitrogen atom towhich they are attached to form a three to twelve membered cyclic,heterocyclic or heteroaryl ring; and wherein in the compound having theformula VII, L is a diradical moiety selected from the group consistingof (C₁-C₂₀)alkyl, (C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl,(C₁-C₂₀)alkoxy/thiol, (C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl,(C₃-C₁₅)heterocyclic and (C₃-C₂₀)cycloalkyl; wherein each of theaforesaid (C₁-C₂₀)alkyl, (C₃-C₂₀)cycloalkyl, (C₂-C₂₀)alkenyl,(C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₃-C₂₀)cycloalkynyl,(C₁-C₂₀)alkoxy/thiol, (C₃-C₂₀)aryl, (C₃-C₁₅)heteroaryl,(C₃-C₁₅)heterocyclic and (C₃-C₂₀)cycloalkyl diradical moieties may besubstituted or unsubstituted.
 2. The salt of claim 1, wherein thepharmaceutically acceptable acid has the following formula:


3. The salt of claim 1, wherein the pharmaceutically acceptable acid hasthe following formula:


4. The salt of claim 1, wherein the pharmaceutically acceptable acid hasthe following formula:


5. The salt of claim 1, wherein the pharmaceutically acceptable acid hasthe following formula:


6. The salt of claim 1, wherein the pharmaceutically acceptable acid hasthe following formula:


7. The salt of claim 1, wherein the pharmaceutically acceptable acid hasone of the following formulas:


8. The salt of claim 1, wherein the pharmaceutically acceptable acid hasthe following formula:


9. A pharmaceutically acceptable composition, comprising the salt ofclaim 1 in contact with at least one pharmaceutically acceptablecarrier.
 10. A method, comprising administering the salt of claim 1 to ahuman.
 11. A pharmaceutically acceptable salt, comprising one or morecompounds having the formula:

wherein X¹, X², X³, and X⁴ each independently represent H, GhyCH—,GhyCCH₃—, or CH₃CO—, with the provisos that X¹, X², X³ and X⁴ are notsimultaneously H; wherein Z is one or more selected from the groupconsisting of: -(A¹)_(a)-(CR²R³)_(x)-(A²)_(b);-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)_(y)-(A²)_(b)-; and-(A¹)_(a)-(CR²R³)_(x)-Q_(m)-(CR⁴R⁵)_(y)-T_(n)-(CR⁶R⁷)_(z)-(A²)_(b); andcombinations thereof; wherein a is selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein b is selected from the groupconsisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein x is selectedfrom the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein yis selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and9; wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, 8, and 9; wherein m is selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, and 9; wherein n is selected from the groupconsisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein A¹ and A² areeach independently selected from the group consisting of —NR⁸(CO)NR⁹—,—(CO)NR⁸—, —NR⁸(CO)—, —NR⁸, —O—, —S—, —S(═O)—, —SO₂—, —SO₂NR⁸—,—NR⁸SO₂—, and salts thereof; wherein Q and T are each independentlyselected from the group consisting of —NR¹⁰(CO)NR¹¹—, —(CO)NR¹⁰—,—NR¹⁰(CO)—, —NR¹⁰—, O—, —S—, —S(═O), —SO₂—, —SO₂NR¹⁰—, —NR¹⁰SO₂—, saltsthereof, branched or unbranched, saturated or unsaturated, substitutedor unsubstituted C₁-C₂₀ alkylene, saturated or unsaturated, substitutedor unsubstituted C₃-C₂₀ cycloalkylene, substituted or unsubstitutedC₅-C₂₅ arylene, and combinations thereof; wherein one or more carbonatoms in any of said alkylene, cycloalkylene or arylene in said Q and/orT may each be independently replaced with one or more heteroatomsselected from the group consisting of nitrogen, oxygen, sulfur, and acombination thereof; and wherein when substituted, said alkylene,cycloalkylene or arylene in said Q and/or T are each independentlysubstituted with one or more substituent groups selected from the groupconsisting of hydroxy, halo, bromo, chloro, iodo, fluoro, —N₃, —CN, —NC,—SH, —NO₂, —NH₂, (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl,(C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic,(C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl,(C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl, perhalo(C₁-C₂₀)alkyl,(C₁-C₂₀)alkyl-O—, phenyl-O—, (C₃-C₂₀)cycloalkyl-O—,(C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—, (C₂-C₂₀)alkenyl-O—,(C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—, (C₅-C₂₀)cycloalkynyl-O—,(C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—, (C₁-C₂₀)alkyl-S—, phenyl-S—,(C₃-C₂₀)cycloalkyl-S—, (C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—,(C₂-C₂₀)alkenyl-S—, (C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—,(C₅-C₂₀)cycloalkynyl-S—, (C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—,(C₁-C₂₀)alkyl-SO₂—, phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—,(C₁-C₂₀)alkoxy-SO₂—, (C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)NH—, (C₃-C₂₀)cycloalkyl-(C═O)NH—,(C₁-C₂₀)alkoxy-(C═O)NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)NH—,perhalo(C₁-C₂₀)alkyl-(C═O)NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O){((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O{-(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-, (C₅-C₂₅)aryl-(C═O{-(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₁₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O), (C₂-C₂₀)alkynyl-NH C═O)—,(C₅-C₂₀)cycloalkynyl-NH—C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—,{phenyl}){(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl}{(C₁-C₂₀)alkyl}N(C═O)—, {(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₅)aryl} {(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl}{phenyl}N—(C═O)—, {(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—,{(C₃-C₂₀)cycloalkenyl} {phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl} {phenyl)}N—C═O)—,{(C₅-C₂₅)aryl} {phenyl}N(C═O)—, {perhalo(C₁-C₂₀)alkyl}{phenyl}N—(C═(O)—, HO—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—,(C₃-C₂₅)heteroaryl-(C═O)—, (C₃-C₂₅)heterocyclic-(C═O)—,(C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀) cycloalkenyl-(C═O)—,(C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O),perhalo(C₁-C₂₀)alkyl-O—(C═O), phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof; wherein each of theaforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl, and (C₅-C₂₅)arylgroups (as substituents on said alkylene, cycloalkylene or arylene ofsaid Q and T) may be optionally and independently substituted by one tofour moieties selected from the group consisting of hydroxy, halo,bromo, chloro, iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂,(C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl,perhalo(C, —C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—,(C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl-SO₂—NH—,(C₅-C₂₅)aryl-SO₂—NH—, perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—,phenyl-NH-1 (C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—,(C₃-C₂₅)heteroaryl-NH—, (C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—,(C₃-C₂₀)cycloalkenyl-NH—, (C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—,(C₁-C₂₀)aryl-NH—, perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—,{phenyl}₂N—, {(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—,{(C₃-C₂₅)heteroaryl}₂N—, {(C₃-C₂₅)heterocyclic}₂N—,{(C₂-C₂₀)alkenyl}₂N—, {(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O—)NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O){((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O){(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O){(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O){(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O){(phenyl)N}-, (C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—,{(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—, {(C₂-C₂₀)alkenyl}{phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₅)aryl} {phenyl}N—(C═O)—,{perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O)—,(C₁-C₁₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)-,(C₂-C₂₀)alkynyl-O—(C═O), (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof; and wherein R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selectedfrom the group consisting of hydrogen, hydroxy, halo, bromo, chloro,iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂, (C₁-C₂₀)alkyl, phenyl,(C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl,(C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl,(C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl,perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₅)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀)cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₁-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀) cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₁-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)cycloalkynyl SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O#NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O)—NH—, (C₂-C₂₀)alkynyl-(C═O)—NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O)—NH—, (C₁-C₂₀)alkyl-(C═O){((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₂-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O-{(phenyl)N}-,(C₂-C₁₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O){(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O)-{(phenyl)N}-,(C₅-C₂₅)aryl-(C═O)-{(phenyl)N}-, perhalo(C₁-C₂₀)alkyl-(C═O){(phenyl)N}-,H₂N(C═O)—, (C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkyl-NH—(C═O)—, (C₁-C₂₀)alkoxy-NH—(C═O)—,(C₃-C₂₅)heteroaryl-NH—(C═O)—, (C₃-C₂₅)heterocyclic-NH—(C═O)—,(C₂-C₂₀)alkenyl-NH—(C═O)—, (C₃-C₂₀) cycloalkenyl-NH—(C═O)—,(C₂-C₂₀)alkynyl-NH—(C═O)—, (C₅-C₂₀)cycloalkynyl-NH—(C═O)—,(C₅-C₂₅)aryl-NH—(C═O)—, perhalo(C₁-C₂₀)alkyl-NH—C═O)—,{C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₁-C₂₀)alkoxy}{(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₅)heteroaryl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl}{(C₁-C₂₀)alkyl}N<C═O)—, {(C₅-C₂₅)aryl} {(C₁-C₂₀)alkyl}N—(C═O)—,{perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {phenyl}₂N—(C═O)—,{(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—, {(C₁-C₂₀)alkoxy}{phenyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl} {phenyl}N—(C═O)—,{(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)-, {(C₂-C₂₀)alkenyl}{phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₀)cycloalkynyl}{phenyl}N—(C═O)—, {(C₅-C₂₅)aryl} {phenyl}N—(C═O)—,{perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O)—,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—, (C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—, (C₅-C₂₅)aryl-(C═O)—,perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₂₀)alkyl-O—(C═O)—,(C₃-C₂₅)heteroaryl-O—(C═O)—, (C₃-C₂₅)heterocyclic-O—(C═O)—,(C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀) cycloalkenyl-O—(C═O)—,(C₂-C₂₀)alkynyl-O—(C═O)—, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O)—, (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof; wherein each of theaforesaid (C₁-C₂₀)alkyl, phenyl, (C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy,(C₃-C₂₅)heteroaryl, (C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl, and (C₅-C₂₅)arylgroups (for said R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ groups)may be optionally and independently substituted by one to four moietiesselected from the group consisting of hydroxy, halo, bromo, chloro,iodo, fluoro, —N₃, —CN, —NC, —SH, —NO₂, —NH₂, (C₁-C₂₀)alkyl, phenyl,(C₃-C₂₀)cycloalkyl, (C₁-C₂₀)alkoxy, (C₃-C₂₅)heteroaryl,(C₃-C₂₅)heterocyclic, (C₂-C₂₀)alkenyl, (C₃-C₂₀) cycloalkenyl,(C₂-C₂₀)alkynyl, (C₅-C₂₀)cycloalkynyl, (C₅-C₂₅)aryl,perhalo(C₁-C₂₀)alkyl, (C₁-C₂₀)alkyl-O—, phenyl-O—,(C₃-C₂₀)cycloalkyl-O—, (C₃-C₂₀)heteroaryl-O—, (C₃-C₂₅)heterocyclic-O—,(C₂-C₂₀)alkenyl-O—, (C₃-C₂₀) cycloalkenyl-O—, (C₂-C₂₀)alkynyl-O—,(C₅-C₂₀)cycloalkynyl-O—, (C₅-C₂₅)aryl-O—, perhalo(C₁-C₂₀)alkyl-O—,(C₁-C₂₀)alkyl-S—, phenyl-S—, (C₃-C₂₀)cycloalkyl-S—,(C₃-C₂₅)heteroaryl-S—, (C₃-C₂₅)heterocyclic-S—, (C₂-C₂₀)alkenyl-S—,(C₃-C₂₀)cycloalkenyl-S—, (C₂-C₂₀)alkynyl-S—, (C₅-C₂₀)cycloalkynyl-S—,(C₅-C₂₅)aryl-S—, perhalo(C₁-C₂₀)alkyl-S—, (C₁-C₂₀)alkyl-SO₂—,phenyl-SO₂—, (C₃-C₂₀)cycloalkyl-SO₂—, (C₁-C₂₀)alkoxy-SO₂—,(C₃-C₂₅)heteroaryl-SO₂—, (C₃-C₂₅)heterocyclic-SO₂—,(C₂-C₂₀)alkenyl-SO₂—, (C₃-C₂₀)cycloalkenyl-SO₂—, (C₂-C₂₀)alkynyl-SO₂—,(C₅-C₂₀)cycloalkynyl-SO₂—, (C₅-C₂₅)aryl-SO₂—, perhalo(C₁-C₂₀)alkyl-SO₂—,H₂N—SO₂—, (C₁-C₂₀)alkyl-NH—SO₂—, phenyl-NH—SO₂—,(C₃-C₂₀)cycloalkyl-NH—SO₂—, (C₁-C₂₀)alkoxy-NH—SO₂—,(C₃-C₂₅)heteroaryl-NH—SO₂—, (C₃-C₂₅)heterocyclic-NH—SO₂—,(C₂-C₂₀)alkenyl-NH—SO₂—, (C₃-C₂₀)cycloalkenyl-NH—SO₂—,(C₂-C₂₀)alkynyl-NH—SO₂—, (C₅-C₂₀)cycloalkynyl-NH—SO₂—,(C₅-C₂₅)aryl-NH—SO₂—, perhalo(C₁-C₂₀)alkyl-NH—SO₂—,{(C₁-C₂₀)alkyl}₂N—SO₂—, {phenyl}₂N—SO₂—, {(C₃-C₂₀)cycloalkyl}₂N—SO₂—,{(C₁-C₂₀)alkoxy}₂N—SO₂—, {(C₃-C₂₅)heteroaryl}₂N—SO₂—,{(C₃-C₂₋₅)heterocyclic}₂N—SO₂—, {(C₂-C₂₀)alkenyl}₂N—SO₂—,{(C₂-C₂₀)alkynyl}₂N—SO₂—, {(C₅-C₂₀)cycloalkynyl}₂N—SO₂—,{(C₅-C₂₅)aryl}₂N—SO₂—, {perhalo(C₁-C₂₀)alkyl}₂N—SO₂—,(C₁-C₂₀)alkyl-SO₂—NH—, phenyl-SO₂—NH—, (C₃-C₂₀)cycloalkyl-SO₂—NH—,(C₁-C₂₀)alkoxy-SO₂—NH—, (C₃-C₂₅)heteroaryl-SO₂—NH—,(C₃-C₂₅)heterocyclic-SO₂—NH—, (C₂-C₂₀)alkenyl-SO₂—NH—,(C₃-C₂₀)cycloalkenyl-SO₂—NH—, (C₂-C₂₀)alkynyl-SO₂—NH—,(C₅-C₂₀)Cycloalkynyl-SO₂—NH—, (C₅-C₂₅)aryl-SO₂—NH—,perhalo(C₁-C₂₀)alkyl-SO₂—NH—, (C₁-C₂₀)alkyl-NH—, phenyl-NH—,(C₃-C₂₀)cycloalkyl-NH—, (C₁-C₂₀)alkoxy-NH—, (C₃-C₂₅)heteroaryl-NH—,(C₃-C₂₅)heterocyclic-NH—, (C₂-C₂₀)alkenyl-NH—, (C₃-C₂₀)cycloalkenyl-NH—,(C₂-C₂₀)alkynyl-NH—, (C₅-C₂₀)cycloalkynyl-NH—, (C₅-C₂₅)aryl-NH—,perhalo(C₁-C₂₀)alkyl-NH—, {(C₁-C₂₀)alkyl}₂N—, {phenyl}₂N—,{(C₃-C₂₀)cycloalkyl}₂N—, {(C₁-C₂₀)alkoxy}₂N—, {(C₃-C₂₅)heteroaryl}₂N—,{(C₃-C₂₅)heterocyclic}₂N—, {(C₂-C₂₀)alkenyl}₂N—,{(C₃-C₂₀)cycloalkenyl}₂N—, {(C₂-C₂₀)alkynyl}₂N—,{(C₅-C₂₀)cycloalkynyl}₂N—, {(C₅-C₂₅)aryl}₂N—, {perhalo(C₁-C₂₀)alkyl}₂N—,(C₁-C₂₀)alkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C₃-C₂₀)cycloalkyl-(C═O)—NH—,(C₁-C₂₀)alkoxy-(C═O)—NH—, (C₃-C₂₅)heteroaryl-(C═O)—NH—,(C₃-C₂₅)heterocyclic-(C═O)—NH—, (C₂-C₂₀)alkenyl-(C═O)—NH—,(C₃-C₂₀)cycloalkenyl-(C═O—NH—, (C₂-C₂₀)alkynyl-(C═O)NH—,(C₅-C₂₀)cycloalkynyl-(C═O)—NH—, (C₅-C₂₅)aryl-(C═O)—NH—,perhalo(C₁-C₂₀)alkyl-(C═O—NH—, (C₁-C₂₀)alkyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,phenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₁-C₂₀)alkoxy-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-, (C₃-C₂₀)cycloalkenyl-(C═O)-{((C₁-C₂₀)alkyl)N}-,(C₂-C₂₀)alkynyl-(C═O)H{((C₁-C₂₀)alkyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O){((C₁-C₂₀)alkyl)N}-,(C₅-C₂₅)aryl-(C═O)-{((C₁-C₂₀)alkyl)N}-,perhalo(C₁-C₂₀)alkyl-C═O)-{((C₁-C₂₀)alkyl)N}-, phenyl-(C═O)—NH—,phenyl-(C═O){(phenyl)N}-, (C₁-C₂₀)alkyl-(C═O{-(phenyl)N}-,(C₃-C₂₀)cycloalkyl-(C═O)-{(phenyl)N}-, (C₁-C₂₀)alkoxy-(C═O{-(phenyl)N}-,(C₃-C₂₅)heteroaryl-(C═O)-{(phenyl)N}-,(C₃-C₂₅)heterocyclic-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkenyl-(C═O)-{(phenyl)N}-,(C₃-C₂₀)cycloalkenyl-(C═O)-{(phenyl)N}-,(C₂-C₂₀)alkynyl-(C═O{-(phenyl)N}-,(C₅-C₂₀)cycloalkynyl-(C═O{-(phenyl)N}-, (C₅-C₂₅)aryl-(C═O){(phenyl)N}-,perhalo(C₁-C₂₀)alkyl-(C═O)-{(phenyl)N}-, H₂N(C═O)—,(C₁-C₂₀)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₃-C₂₀)cycloalkyl-NH—(C═O)—,(C₁-C₂₀)alkoxy-NH—(C═O)—, (C₃-C₂₅)heteroaryl-NH—(C═O)—,(C₃-C₂₅)heterocyclic-NH—(C═O)—, (C₂-C₂₀)alkenyl-NH—(C═O)—,(C₃-C₂₀)cycloalkenyl-NH—(C═O)—, (C₂-C₂₀)alkynyl-NH—(C═O)—,(C₅-C₂₀)cycloalkynyl-NH—(C═O)—, (C₅-C₂₅)aryl-NH—(C═O)—,perhalo(C₁-C₂₀)alkyl-NH—(C═O)—, {C₁-C₂₀)alkyl}₂N—(C═O)—, {phenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {(C₁-C₂₀)alkyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{(C₁-C₂₀)alkyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {(C₁-C₂₀)alkyl)}N—(C═O)—, {(C₅-C₂₅)aryl}{(C₁-C₂₀)alkyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {(C₁-C₂₀)alkyl}N—(C═O)—,{phenyl}₂N—(C═O)—, {(C₃-C₂₀)cycloalkyl} {phenyl}N—(C═O)—,{(C₁-C₂₀)alkoxy} {phenyl}N—(C═O)—, {(C₃-C₂₅)heteroaryl}{phenyl}N—(C═O)—, {(C₃-C₂₅)heterocyclic} {phenyl}N—(C═O)—,{(C₂-C₂₀)alkenyl} {phenyl}N—(C═O)—, {(C₃-C₂₀)cycloalkenyl}{phenyl}N—(C═O)—, {(C₂-C₂₀)alkynyl} {phenyl}N—(C═O)—,{(C₅-C₂₀)cycloalkynyl} {phenyl}N—(C═O)—, {(C₅-C₂₅)aryl}{phenyl}N—(C═O)—, {perhalo(C₁-C₂₀)alkyl} {phenyl}N—(C═O)—, HO—(C═O)—,(C₁-C₂₀)alkyl-(C═O)—, (C₃-C₂₅)heteroaryl-(C═O)—,(C₃-C₂₅)heterocyclic-(C═O)—, (C₂-C₂₀)alkenyl-(C═O)—,(C₃-C₂₀)cycloalkenyl-(C═O)—, (C₂-C₂₀)alkynyl-(C═O)—,(C₅-C₂₅)aryl-(C═O)—, perhalo(C₁-C₂₀)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₂₀)alkyl-O—(C═O)—, (C₃-C₂₅)heteroaryl-O—(C═O)—,(C₃-C₂₅)heterocyclic-O—(C═O)—, (C₂-C₂₀)alkenyl-O—(C═O)—, (C₃-C₂₀)cycloalkenyl-O—(C═O)—, (C₂-C₂₀)alkynyl-O—(C═O)-, (C₅-C₂₅)aryl-O—(C═O)—,perhalo(C₁-C₂₀)alkyl-O—(C═O)—, phenyl-O—(C═O), (C₁-C₂₀)alkyl-(C═O)—O—,(C₃-C₂₅)heteroaryl-(C═(O)—O—, (C₃-C₂₅)heterocyclic-(C═O)—O—,(C₂-C₂₀)alkenyl-(C═O)—O—, (C₃-C₂₀)cycloalkenyl-(C═O)—O—,(C₂-C₂₀)alkynyl-(C═O)—O—, (C₅-C₂₅)aryl-(C═O)—O—, phenyl-(C═O)—O—,perhalo(C₁-C₂₀)alkyl-(C═O)—O—, and salts thereof; and wherein twoindependently chosen R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹alkyl-containing groups may be taken together with any atom to whichthey are attached to form a three to forty membered cyclic, heterocyclicor heteroaryl ring; as a salt of at least one pharmaceuticallyacceptable acid selected from the group consisting of compounds havingthe following formulas:

wherein each C* independently represents a potentially chiral carbonthat can be in either the D or L enantiomeric configuration; whereineach R is independently unsubstituted or substituted and selected fromthe group consisting of Y—, Y—O—, Y—S—, Y—SO₂—, (Y)₂—N—SO₂—, Y—(C═O)—,Y—(C═O)—O—, YO—(C═O)—, (Y)₂—N—, Y—(C═O)—(Y—N)—, (Y—(C═O))₂—N—,Y—(SO₂)—(Y—N)—, or (Y—(SO₂))₂—N—; each Y being independently selectedfrom the group consisting of hydrogen, carboxyl, halo, hydroxyl, thiol,nitro, amine, NC—, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₃-C₆) cycloalkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkynyl,(C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and (C₃-C₅)heterocyclic;wherein each of the aforesaid (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₂-C₆)alkenyl, (C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkynyl, (C₁-C₆)alkoxy, (C₅-C₇)aryl, (C₃-C₅)heteroaryl, and(C₃-C₅)heterocyclic substituents may be substituted or unsubstituted;wherein two independently chosen Y alkyl-containing groups may be takentogether with any nitrogen atom to which they are attached to form athree to twelve membered cyclic, heterocyclic or heteroaryl ring; andwherein in the compound having the formula VII, L is a diradical moietyselected from the group consisting of (C₁-C₂₀)alkyl, (C₃-C₂₀)cycloalkyl,(C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl,(C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol, (C₃-C₂₀)aryl,(C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and (C₃-C₂₀)cycloalkyl; whereineach of the aforesaid (C₁-C₂₀)alkyl, (C₃-C₂₀)cycloalkyl,(C₂-C₂₀)alkenyl, (C₃-C₂₀)cycloalkenyl, (C₂-C₂₀)alkynyl,(C₃-C₂₀)cycloalkynyl, (C₁-C₂₀)alkoxy/thiol, (C₃-C₂₀)aryl,(C₃-C₁₅)heteroaryl, (C₃-C₁₅)heterocyclic and (C₃-C₂₀)cycloalkyldiradical moieties may be substituted or unsubstituted.
 12. The salt ofclaim 11, wherein the pharmaceutically acceptable acid has the followingformula:


13. The salt of claim 11, wherein the pharmaceutically acceptable acidhas the following formula:


14. The salt of claim 11, wherein the pharmaceutically acceptable acidhas the following formula:


15. The salt of claim 11, wherein the pharmaceutically acceptable acidhas the following formula:


16. The salt of claim 11, wherein the pharmaceutically acceptable acidhas the following formula:


17. The salt of claim 11, wherein the pharmaceutically acceptable acidhas one of the following formulas:


18. The salt of claim 11, wherein the pharmaceutically acceptable acidhas the following formula:


19. A pharmaceutically acceptable composition, comprising the salt ofclaim 11 in contact with at least one pharmaceutically acceptablecarrier.
 20. A method, comprising administering the salt of claim 11 toa human.